title: β-Amyloid-evoked apoptotic cell death is mediated through MKK6-p66shc pathway.
abstract: We have previously shown the involvement of p66shc in mediating apoptosis. Here, we demonstrate the novel mechanism of β-Amyloid-induced toxicity in the mammalian cells. β-Amyloid leads to the phosphorylation of p66shc at the serine 36 residue and activates MKK6, by mediating the phosphorylation at serine 207 residue. Treatment of cells with antioxidants blocks β-Amyloid-induced serine phosphorylation of MKK6, reactive oxygen species (ROS) generation, and hence protected cells against β-Amyloid-induced cell death. Our results indicate that serine phosphorylation of p66shc is carried out by active MKK6. MKK6 knock-down resulted in decreased serine 36 phosphorylation of p66shc. Co-immunoprecipitation results demonstrate a direct physical association between p66shc and WT MKK6, but not with its mutants. Increase in β-Amyloid-induced ROS production was observed in the presence of MKK6 and p66shc, when compared to triple mutant of MKK6 (inactive) and S36 mutant of p66shc. ROS scavengers and knock-down against p66shc, and MKK6 significantly decreased the endogenous level of active p66shc, ROS production, and cell death. Finally, we show that the MKK6-p66shc complex mediates β-Amyloid-evoked apoptotic cell death.
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar, 190006, Kashmir, India.
authors.forename: Muneesa
authors.initials: M
authors.lastname: Bashir
authors.forename: Arif A
authors.initials: AA
authors.lastname: Parray
authors.forename: Rafia A
authors.initials: RA
authors.lastname: Baba
authors.forename: Hina F
authors.initials: HF
authors.lastname: Bhat
authors.forename: Sehar S
authors.initials: SS
authors.lastname: Bhat
authors.forename: Umar
authors.initials: U
authors.lastname: Mushtaq
authors.forename: Khurshid I
authors.initials: KI
authors.lastname: Andrabi
authors.forename: Firdous A
authors.initials: FA
authors.lastname: Khanday
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000473:pathology; D006801:Humans; D048669:MAP Kinase Kinase 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000633:toxicity; D010766:Phosphorylation; D010768:Phosphoserine / Q000737:chemistry; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins / Q000502:physiology*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C074636:amyloid beta-protein (25-35); C090308:amyloid beta-protein (40-1); D010768:Phosphoserine; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; C482567:Map2k6 protein, mouse